In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex.

In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4'-dimethoxy-2-2'-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO4)2], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO4)2] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with Kb values in the range of 103-104 M-1, with [Cu(4-MH)(dmb)(ClO4)2] showing the highest Kb value (1.45 × 104 M-1). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO4)2] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.

Three new platinum complexes containing fluoroquinolones and DMSO: Cytotoxicity and evaluation against drug-resistant tuberculosis.

This work describes the synthesis, characterization and biological evaluation of three platinum complexes of the type [Pt(DMSO)(L)Cl]Cl, in which L represents a fluoroquinolone, namely, ciprofloxacin (cpl), ofloxacin (ofl), or sparfloxacin (spf). The new complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRESIMS) and 1H, 13C and 195Pt NMR (nuclear magnetic resonance). The spectral data suggest that the fluoroquinolones act as bidentate ligands coordinated to Pt(II) through the nitrogen atoms of the piperazine ring. Microbiological assays against wild type Mycobacterium tuberculosis (ATCC 27294) showed that all complexes have been very potent, exhibiting antitubercular potency at concentrations <2 µM, although none of the complexes presented higher potency than established anti-TB drugs. As to the resistant strains, the complex with sparfloxacin, [Pt(DMSO)(spf)Cl]Cl exhibited the best potential against most Mycobacterium tuberculosis clinical isolates. The cytotoxicity of these compounds was also evaluated in three breast cell lines: MCF-10 (a healthy cell), MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both tumor cell lines, [Pt(DMSO)(spf)Cl]Cl was more active and more selective than cisplatin. Flow cytometry analysis revealed that [Pt(DMSO)(spf)Cl]Cl induced late apoptotic cell death in MDA-MB-231 cells.

Novel copper(II) complexes with hydrazides and heterocyclic bases: Synthesis, structure and biological studies.

Five new copper(II) complexes of the type [Cu(NO)(NN)(ClO4)2], in which NO=4-fluorophenoxyacetic acid hydrazide (4-FH) or 4-nitrobenzoic hydrazide (4-NH) and NN=1,10-phenanthroline (phen), 4-4'-dimethoxy-2-2'-bipyridine (dmb) or 2,2-bipyridine (bipy) were synthesized and characterized using various spectroscopic methods. The X-ray structural analysis of one representative compound indicates that the geometry around the copper ion is distorted octahedron, in which the ion is coordinated to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. Two perchlorate anions occupy the apical positions, completing the coordination sphere. The cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF-7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and [Cu(phen)2]2+. Considering the cytotoxicity results, further investigations for the compounds [Cu(4-FH)(phen)(ClO4)2] I and [Cu(4-NH)(phen)(ClO4)2]∙H2O III were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38×104 and 2.62×104, respectively. These compounds were also evaluated against wild type Mycobacterium tuberculosis (ATCC 27294) and exhibited antimycobacterial activity, displayed MIC values lower than those of the corresponding free ligands.

Centrosymmetric resonance-assisted intermolecular hydrogen bonding chains in the enol form of ß-diketone: Crystal structure and theoretical study.

Isobenzofuran-1(3H)-ones (phtalides) are heterocycles that present a benzene ring fused to a γ-lactone functionality. This structural motif is found in several natural and synthetic compounds that present relevant biological activities. In the present investigation, the 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohexen-1-yl)isobenzofuran-1(3H)-one was characterized by single-crystal X-ray analysis. In the crystal structure, there are two molecules per asymmetric unit. One of them exhibits resonance assisted hydrogen bonds (RAHBs). Semi-empirical and DFT calculations were performed to obtain electronic structure and π-delocalization parameters, in order to better understand the energy stabilization of RAHBs in the crystal packing of the studied molecule. The structural parameters showed good agreement between theoretical and experimental data. The theoretical investigation revealed that the RAHBs stabilization energy is directly related to the electronic delocalization of the enol form fragment. In addition, RAHBs significantly affected the HOMO and charge distribution around the conjugated system.

6-Meth-oxyisobenzofuran-1(3H)-one.

In the title compound, C(9)H(8)O(3), the mol-ecular skeleton is almost planar [r.m.s. deviation = 0.016 (2) Å]. Weak inter-molecular C-H⋯O and C-H⋯π inter-actions consolidate the crystal packing, with the mol-ecules stacking in the [101] direction.

Bis(tetra-phenyl-phospho-nium) bis-[N-(trifluoro-methyl-sulfon-yl)dithio-carbimato(2-)-κS,S']zincate(II).

The title salt, (C(24)H(20)P)(2)[Zn(C(2)F(3)NO(2)S(3))(2)], consists of a complex dianion and two tetra-phenyl-phospho-nium cations. The Zn(II) ion displays a distorted tetra-hedral coordination environment with four S atoms from two S,S'-chelated N-(trifluoro-methyl-sulfonyl-)dithio-carbimate anions. In the crystal, besides the ionic inter-action of the oppositely charged ions, inter-molecular C-H⋯O inter-actions between cations and anions are observed. One of the cations inter-acts with an inversion-related equivalent by π-π stacking between phenyl rings, with a centroid-centroid distance of 3.932 (4) Å.

5-Meth-oxy-2-benzofuran-1(3H)-one.

In the title compound, C9H8O3, the mol-ecular skeleton is almost planar, with an r.m.s. deviation of 0.010 (2) Å. In the crystal, weak C-H⋯O hydrogen bonds connect the mol-ecules into a two-dimensional network parallel to the ac plane.

N-(2-Nitro-oxyeth-yl)picolinamide.

In the title mol-ecule, C(8)H(9)N(3)O(4), the amide group is involved in the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, mol-ecules related by translation along the a axis are linked into chains via weak inter-molecular C-H⋯O inter-actions.